Project Summary/Abstract Despite improved therapies over the last 15 years, the plasma cell neoplasm multiple myeloma (MM) remains incurable. The majority of patients ultimately relapse and succumb to drug-resistant disease. In MM, the bulk of cancer cells lack the stem cell-like properties required for the maintenance of clonogenic growth over time (i.e., self-renewal), and cells that have enhanced self-renewal will contribute to relapse and disease progression. Therefore, targeting the cells responsible for self-renewal will lead to improved outcomes. However, the development of stem cell directed therapies in MM is impeded by our current lack of understanding in the molecular drivers and the phenotype of cells that are responsible for self-renewal. In newly diagnosed MM, self-renewal and differentiation parallels normal B-cell hierarchy in that B-cell progenitors, not differentiated plasma cells, display enhanced self-renewal potential. However, not all MM tumors exhibit this hierarchal organization and we have shown that differentiated plasma cells from relapsed/refractory MM also possess stem cell properties. We have also found that aberrant RAS pathway activation, which is predominantly found in more differentiated plasma cells and associated with disease progression, drives MM clonogenic growth, self-renewal, and proliferation. We hypothesize that the acquisition oncogenic drivers, including mutant RAS, drive MM disease progression by conferring self-renewal in differentiated progenitor compartments. Accordingly, we propose to: 1) Determine the role of oncogenic RAS in MM disease progression in a murine model and 2) Determine the relationship between oncogenic RAS and stem cell properties in MM patients. The expectation is that these studies will define the relationship between disease stage, RAS mutations, phenotype, and stem cell functions and lead to better treatments for advanced MM patients where there are currently few effective therapies. Dr. Gocke?s long-term goal is to become an independent laboratory physician-scientist that determines the fundamental drivers of relapse and disease progression and translates these findings into potential therapies for MM patients. Through this proposal Dr. Gocke will acquire the additional research skills and career experience needed to reach this goal. In Aim 1, Dr. Gocke will learn how to perform clinically relevant murine modeling of MM that can lead to a better understanding of disease evolution; and in Aim 2, he will acquire the skills needed to utilize clinical specimens to determine the functional impact of genomic changes and cellular phenotype on stem cell properties and response to targeted therapies. Acquiring these skills will be critical to developing a relevant, impactful translational research program in MM.